Parenteral nutrients are administered in peripheral or central veins to supplement a patient's diet. Total parenteral nutrition is a recent advance in the maintenance of patients having an impaired gastrointestinal capacity. Such patients may have lost the use of a large portion of their intestinal tract either permanently or due to surgical intervention as may be required in cancer or Crohn's disease, or temporarily as a result of chemotherapeutic drugs or in the treatment of diverticulitis. Total parenteral nutrition is utilized as an adjunct therapy for the critically ill patient who has a generally increased metabolic rate and is unable to eat. The intent of the nutritional support is to prevent the loss of body nitrogen and the resulting complications of multiple organ failure, infection and increased chances of morbidity and mortality.
The energy source most commonly used for intravenous feeding has been glucose because carbohydrates are important for oral diets. However, glucose has not been as effective as was originally anticipated, and more importantly, the route of administration bypasses the normal digestive regulatory mechanisms for controlling blood sugar. Thus, continued intravenous administration (i.v.) of glucose generally results in high blood glucose levels which may have adverse consequences to the patient (particularly diabetics). Additional problems which can arise from i.v. glucose administration include fatty liver, respiratory stress, immune function inhibition, increased insulin secretion and undesirable metabolic regulation. Furthermore, skeletal muscle tissue is not well protected from degradation upon glucose administration to patients with trauma.
Due to these complications, it has been impossible to intravenously administer all the nutritional needs of the human body. This shortcoming poses a formidable problem to clinicians who must attempt such parenteral support. The problem is not merely one of administering a correct amount of calories and nutrients, but rather deals with providing these nutrients in a form which will suppress the breakdown of body proteins (catabolism) such as muscle tissue. This problem extends to trauma patients, where the goal is to provide supplemental energy sources to meet the increased energetic demands of the healing process.
Attempts have been made to find substitutes for glucose that do not instill an insulin response and that do not break down the body proteins. Substrates with metabolic properties very similar to glucose but lacking a significant insulin response are the so-called ketone bodies, 3-hydroxybutyrate and acetoacetate. U.S. Pat. No. 5,093,044 discloses water insoluble glycerol esters containing two or three acetoacetyl groups or two or three hydroxybutyryl groups. These compounds are water insoluble and thus must be administered enterally or parenterally in emulsion form. Other glyceride esters disclosed in this patent are based on pyruvic acid and lactic acid. The following publications disclose the water soluble monoglyceride of acetoacetic acid that is metabolized in vivo. European Pat. Application 0348664 (1990); R. H. Birkhahn et al., J. Nutrition, 109, 1168 (1979); S. A. Kripke et al., J. of Surgical Research, 44, 436 (1988); R. H. Birkhahn et al., J. of Surgical Research, 47, 427 (1989); S. Tanaka, J. of the Osaka City Medical Center, 38, 781 (1989).
W090/02548 discloses an energy substrate containing alpha-hydroxycarboxylic acid and glycerol ester.
U.S. Pat. No. 4,997,976 discloses the use of 1,3-butanediol acetoacetate in parenteral oral nutrition.
U.S. Pat. No. 4,665,057 discloses a variety of nutrient monoesters of saccharides and monoglycerides containing fatty acids of four to ten carbon atoms.
U.S. Pat. No. 4,701,443 discloses certain nutrient polyesters based on dibasic acids such as succinic acid which may also contain moieties such as sugars, acetoacetyl groups and 3-hydroxybutyryl groups.
T. Nishihata et al., Chem. Pharm. Bull., 32,2025(1984); T. Nishihata et al, Chem. Pharm. Bull., 72,280(1983); and JP Kokai 113,723(1980) disclose compounds such as glycerol 1,3-diacetoacetate, 1,2-isopropylideneglyceryl 3-acetoacetate, and 2,3-isopropylidene-1-acetate that enhance the absorption of certain agents in the intestine.
In light of the above, it would be very desirable to be able to produce and use water soluble non-glucose based parenteral nutrients that are at least as effective as glucose in supporting body weight with less of an insulin response and less protein degradation.